The synthesis of sulfone compounds and in particular β-aminosulfone compounds is of interest because these compounds themselves can have favourable properties and may furthermore be useful in the preparation of compounds with a potential for biological activities. β-Aminosulfones play an important role in physiological processes and are for instance used as intermediates in the synthesis of α-amino acids, amino alcohols, uridines, adenosines, alkaloids, β-lactams, etc.
β-Aminophenethyl sulfone derivatives have shown potential to treat inflammatory diseases, in particular globally relevant inflammatory diseases such as arthritis and related arthritic conditions such as psoriatic arthritis, psoriasis, and Crohn's disease. Specifically, this class of compounds shows promising potential as selective phosphodiesterase 4 (PDE IV or PDE4) type inhibitors.
The synthesis of sulfone compounds and in particular β-aminosulfone compounds may thus provide useful intermediates for the synthesis of anti-inflammatory agents, preferably active for treatment of psoriatic arthritis, and in particular for the synthesis of apremilast. Apremilast, which is N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide, is an inhibitor of PDE4. Apremilast specifically inhibits PDE4 and spontaneous production of TNF-α from human rheumatoid synovial cells and has anti-inflammatory activity.
WO 00/25777 A1 describes the synthesis of the racemate of apremilast and derivatives thereof. WO 03/080049 A1 describes the optical resolution of a racemic β-aminosulfone intermediate using stoichiometric amounts of enantiomerically pure chiral amino acids to obtain apremilast. However, in both cases the overall synthetic routes are lengthy requiring several steps and use expensive as well as hazardous materials. In WO 2010/030345 A2 a synthesis of apremilast is described which inter alia includes the formation of a benzonitrile derivative and furthermore a reduction step.
WO 2013/126360 A2 and WO 2013/126495 A2 describe processes to produce apremilast which include the preparation of enantiomerically pure chiral β-aminosulfone intermediates using expensive as well as toxic materials such as metal catalysts, ligands or chiral auxiliaries.
The object of the present invention is to provide short, simple, cost-effective, environmentally friendly and industrially suitable synthetic processes for preparing β-amino sulfone, sulfoxide and sulfide intermediates useful for the preparation of sulfone group containing isoindoline-based compounds, in particular apremilast.